Antinociceptive role of neurotensin receptor 1 in rats with chemotherapy-induced peripheral neuropathy

Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of anti-cancer drugs. Neurotensin receptors (NTSRs) are widely distributed within the pain circuits in the central nervous system. The purpose of this study was to determine the role of NTSR1 by examining the effects of an NTSR1 agonist in rats with CIPN and investigate the contribution of spinal serotonin receptors to the antinociceptive effect.

Methods: Sprague-Dawley rats (weight 150-180 g) were used in this study. CIPN was induced by injecting cisplatin (2 mg/kg) once a day for 4 days. Intrathecal catheters were placed into the subarachnoid space of the CIPN rats. The antiallodynic effects of intrathecally or intraperitoneally administered PD 149163, an NTSR1 agonist, were evaluated. Furthermore, the levels of serotonin in the spinal cord were measured by high-performance liquid chromatography.

Results: Intrathecal or intraperitoneal PD 149163 increased the paw withdrawal threshold in CIPN rats. Intrathecal administration of the NTSR1 antagonist SR 48692 suppressed the antinociceptive effect of PD 149163 given via the intrathecal route, but not the antinociceptive effect of intraperitoneally administered PD 149163. Intrathecal administration of dihydroergocristine, a serotonin receptor antagonist, suppressed the antinociceptive effect of intrathecally administered, but not intraperitoneally administered, PD 149163. Injecting cisplatin diminished the serotonin level in the spinal cord, but intrathecal or intraperitoneal administration of PD 149163 did not affect this reduction.

Conclusions: NTSR1 played a critical role in modulating CIPN-related pain. Therefore, NTSR1 agonists may be useful therapeutic agents to treat CIPN. In addition, spinal serotonin receptors may be indirectly involved in the effect of NTSR1 agonist.

Keywords: Cisplatin; Dihydroergocristine; Hyperalgesia; Neuralgia; Neurotensin; PD 149163; Peripheral Nervous System Diseases; SR 48692; Serotonin Antagonists; Spinal Cord.

Fig. 1

Antinociceptive effect of intrathecal PD 149163 in chemotherapy-induced peripheral neuropathic rats. (A, B) The effect of intrathecal PD 149163 (PD: 0, 3, 10, and 30 ng) on the hind paw withdrawal threshold (PWT) to von Frey filaments. (C, D) The effect of intrathecal SR 48692 (SR: 0 or 100 µg) on the antiallodynic effect caused by PD 149163 (30 ng). SR 48692 was delivered 10 minutes before PD 149163 administration. Each line or bar represents mean ± standard error of 6-7 rats. MPE: maximum possible effect, i.t.: intrathecal administration. *P < 0.05 compared to vehicle. ^#P < 0.05 compared to PD 149163 (i.t.)-treated group.

Fig. 2

Antinociceptive effect of intraperitoneal PD 149163 in chemotherapy-induced peripheral neuropathic rats. (A, B) The effect of intraperitoneal PD 149163 (PD: 0, 0.03, 0.1, and 0.3 mg/kg) for the hind paw withdrawal threshold (PWT) to von Frey filaments. (C, D) The effect of intrathecal SR 48692 (SR: 0 or 100 µg) on the antiallodynic effect caused by intraperitoneal PD 149163 (0.3 mg/kg). SR 48692 was delivered 10 minutes before PD 149163 administration. Each line or bar represents mean ± standard error from 6 rats. MPE: maximum possible effect, i.t.: intrathecal administration, i.p.: intraperitoneal administration. *P < 0.05 compared to vehicle.

Fig. 3

Association between the serotonin (5-hydroxytryptamine) receptor and the antinociceptive effect of intraperitoneal or intrathecal administration of PD 149163. (A, B) The effect of intrathecal dihydroergocristine (DHE: 0 or 30 µg) on the antinociceptive effect of intraperitoneal PD 149163 (PD: 0.3 mg/kg). (C, D) The effect of intrathecal dihydroergocristine (30 µg) on the antinociceptive effect of intrathecal PD 149163 (30 ng). Dihydroergocristine was delivered 10 minutes before PD 149163 administration. Each line or bar represents mean ± standard error of 6-7 rats. PWT: paw withdrawal threshold, MPE: maximum possible effect, i.t.: intrathecal administration, i.p.: intraperitoneal administration. *P < 0.05 compared to vehicle. ^#P < 0.05 compared to PD 149163 (i.t.)-treated group.

Fig. 4

The levels of serotonin (5-hydroxytryptamine, 5-HT) in the spinal cord of chemotherapy-induced peripheral neuropathic (CIPN) rats. The rats were divided into four groups: Naïve group, CIPN group, CIPN group treated with intrathecal PD 149163 (PD), CIPN group treated with intraperitoneal PD 149163. Each bar represents mean ± standard error of 6 rats. i.t.: intrathecal administration, i.p.: intraperitoneal administration. *P < 0.05 compared to naïve rats.